Indole-2-carboxylates

ABSTRACT

Compounds of the class of 2,3,4,5-tetrahydro-1H-1,4diazepino(1,2a)indoles useful for their pharmacological properties and novel intermediates used in the syntheses thereof.

United States Patent [1 1 3,689,503

Reynolds et al. Sept. 5, 1972 [54] INDOLE-Z-CARBOXYLATES [58] Field ofSearch ..260/326.l3 R, 326.14 R

[72] Inventors: Brian E. Reynolds, Dresher, Pa.

19025; John R. Carson, Norris- [56] References cued town, Pa. '19401[73] Ass igfiee: M cN illabofiito'iiesfinc. u al OTHER PUBOZICATIONS B th .A 4:6 1950. 22 Filed: July 30, 1970 e e C em bs 4 [2]] Appl. No.:64,925 Primary Examiner-Alex Mazel Assistant ExaminerJoseph A. NarcavageRelated Appllcatlon Data Attorney-Robert L. Minier and Salvatore R.Conte [60] Division of Ser. No. 828,727, May 28, 1969,

which is a continuation-in-part of Ser. No. [57] ABSTRACT 734532 June 5,19681 abandoned- Compounds of the class of 2,3,4,5-tetrahydro-lH-l,4- 52us. Cl ..260/326.13 R, 'd'azepmonzahndmes useful for pharmawkg" 260/239BC, 260/239 3T,

260/326. 14%",224/244, 424/274 Int. Cl. ..C07d 27/56 ea] properties' mlnovel intermediates used in the syntfiesesthereo.

6 Claims, No Drawings INDOLE-2-CARBOXYLATES This is a divisionalapplication of my co-pending application Ser. No. 828,727, filed May 28,1969, which in turn is a continuation-in-part of application Ser. No.734,532, filed June 5, 1968, now abandoned.

SUMMARY:

An object of this invention is to provide a novel class ofdiazepinoindoles, in particular,2,3,4,5-tetrahydro-loxo-ll-l-l,4-diazepino[ l,2a]indoles and thecorresponding reduced and 2-lower alkanoyl derivatives thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS:

The novel 2,3,4,5-tetrahydro-lH-l,4-diazepino[1,2a ]-indoles of thisinvention may be structurally represented by the following formulas:

R R R and /Y /W UWRI L) R I (I-a) 7 V wherein R is a member selectedfrom the group consisting of hydrogen, lower alkoxy, chloro and fluoro,R is a member selected from the group consisting of hydrogen, loweralkyl and phenyl, R, is a member selected from the group consisting ofhydrogen, lower alkyl, di-(lower alkyl)-amino-lower alkyl, di-(loweralkyl)-amidomethyl, benzyl and p-tolylmethyl, and R" is a memberselected from the group consisting of hydrogen, lower alkyl, di-(loweralkyl)-amino-lower alkyl, benzyl, p-tolylmethyl and lower alkanoyl. Thetherapeutically active, non-toxic acid addition salts of the foregoingbasic nitrogen containing compounds are also embraced within the scopeof this invention, as are several novel intermediates used in thesyntheses of said compounds (I-a).

As used herein, lower alkyl, lower alkoxy and lower alkanoyl may bestraight or branch chained saturated hydrocarbons having from one toabout six carbon atoms, such as for example, methyl, ethyl, propyl,isopropyl, butyl, pentyl, hexyl and the like alkyls, and respectively,the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, etc., and alkanoyls such as forrnyl, acetyl, propionyl,isopropionyl, butyryl, etc.

The therapeutically active non-toxic acid addition salts of the basicnitrogen containing compounds are prepared by treatment with anappropriate acid such as an inorganic acid, e.g., hydrochloric,hydrobromic, hydriodic, sulfuric, nitric, phosphoric and the like; or anorganic acid such as acetic, propionic, glycolic, lactic, pyruvic,malonic, succinic, maleic, malic, fumaric, tartaric, pamoic, citric,benzoic, mandelic, cinnamic, cyclohexylsulfamic, methane sulfonic,benzene sulfonic, salicylic, 2-phenoxy-benzoic and the like. Conversely,the salt form may be converted in the usual manner into the free base bytreatment with alkali.

The l-oxo diazepinoindoles of formula (Ia) demonstrate blood pressurelowering properties upon intravenous administration in anesthetizeddogs. For example, a decrease in blood pressure of about 30-70 in asuitable high boiling solvent such as xylene,

preferably under reflux conditions, to yield the corresponding formula(l-a) compounds with R, equal to hydrogen. Alternatively, thesecompounds may be prepared by cyclization of a lower alkyl l-(3-aminopropyl)-indole-2-carboxylate of formula (lll) using a base such assodium ethoxide in a solvent such as ethanol. The foregoing reactionschemes may be illustrated by the following diagram in which the symbolsR and R have the same meaning previously indicated:

k N COOaI yl (II)v l CHQCHQCHZNHC OCH; NaH lxylene NaOEt III COOalkylEton Conventional alkylation of the thus-obtained 2-unsubstitutedl-oxo-diazepinoindole with an appropriate alkylating agent affords theother compounds of form ula (l-a) wherein R, is other than hydrogen.Alkylation is readily achieved by first producing the correspondinganion by treatment with a suitable base, e. g., an alkali metal hydride,amide or alkoxide such as sodium hydride, sodamide and potassiumt-butoxide, respectively, followed by treatment with an appropriatealkylating agent of the formula X-R, wherein X is chloro or bromo and R'is the same as R, except for hydrogen, such as a lower alkyl halide, adi-(lower alkyl)-amino-lower alkyl halide, a di-(lower alkyl)-amidomethyl halide, a benzyl halide or a p-tolylmethyl halide. Thealkylation may be carried out in a variety of polar or nonpolar solventssuch as the lower alkanols, e.g., methanol, ethanol and the like; etherssuch as diethyl ether, dioxane and the like; dimethylformamide; oraromatic hydrocarbons such as benzene, toluene, xylene and the like. Theforegoing alkylation procedure may be illustrated as follows:

The compounds of formula (l-b), wherein R" is hydrogen, lower alkyl,di-(lower alkyl)-amino-lower alkyl, benzyl or p-tolylmethyl, are readilyobtained by reduction of the 0x0 function of the corresponding compoundsof formula (l-a), i.e., where R, is other of formula (I-a), wherein R isother than di-(lower alkyl)-amidomethyl, in addition to their utility asblood pressure lowering agents, are useful as synthetic inter--mediates.

Conventional acylation of those compounds of formula (I-b), wherein R"is hydrogen, affords the corresponding compounds of formula (I-b) inwhich R" is lower alkanoyl. A lower alkanoic acid halide, preferably thechloride, or anhydride is employed as the acylating agent. With theformer, a suitable base, such as an alkali metal carbonate, may beadvantageously employed as an acceptor of the halogen acid producedduring the reaction.

The compounds of formula (I-b) possess interesting and usefulproperties. For example, those compounds in which R and R are asinitially described and R" is lower alkanoyl have been found to possesscentral nervous system depressant activity in laboratory animals,

' as demonstrated in mice by a decrease in motor activity at doses of30-300 mg/kg i.p. and ataxia at about 100 mg/kg i.p. Those compounds inwhich R and R are as initially described and R" is lower alkyl,di-(lower alkyl)-amino-lower alkyl, benzyl or p-tolylmethyl possessblood pressure lowering properties, as demonstrated by a decrease ofabout -120 mm. Hg when administered IV. to anesthetized dogs in a doseof 10 mg/kg body weight. Those compounds in which R and R are as,initially described and R is hydrogen have already been shown to beuseful as starting materials for the corresponding 2-(lower alkanoyl)derivatives of formula (I-b). In addition, several of theseZ-unsubstituted compounds have useful pharmacological properties. Forexample, when R is hydrogen or lower alkoxy, and R' and R" are eachhydrogen, pulmonary vasodilator properties are observed, similar to andequal in activity to about -70 percent of the pulmonary vasodilatingactivity of arninophylline upon I.V. administration to 4 anesthetizeddogs at a dose of 5 mg/kg body weight; and, when R is hydrogen orchloro, R is lower alkyl, and R is hydrogen, a lowering of bloodpressure in anesthetized dogs is observed of about 60-80 mm. Hg

upon i.v. administration of 10 mg/kg body weight.

In view of their novelty and usefulness in the syntheses herein, theintermediate compounds of formula (II) constitute a further aspect ofthis invention, as do the intermediate compounds of formula (III) inwhich R' is phenyl.

The formula (II) compounds may be prepared by the reductive amidation ofa corresponding lower alkyl 1- (B-cyano-ethyl)-indole-2-carboxylate(IV), for example, by hydrogenating the latter in the presence of aceticanhydride using a catalyst such as Raney nickel.

The intermediate compounds of formula (III) may be prepared by reductionof the nitrile function in the formula (IV) compounds, for example, withborane in a suitable organic solvent such as tetrahydrofuran or byhydrogenation using a catalyst such as Raney nickel ina solvent such asethanol in the presence of a small amount of ammonia. The compounds offormula (IV), which also possess novelty when R is phenyl, may beprepared by reacting a lower alkyl indole-2-carboxylate of formula (V)with acrylonitrile under standard cyanoethylation conditions, forexample, in dioxane solution in the presence of a base such asbenzyltrimethylammonium hydroxide. The foregoing reactions may befurther illustrated by the following schematic diagram in which R and Rare as initially described:

R R R CHFOHCN C O Oalkyl dioxane base C OOalkyl N i CHzCHzCN anhydridelborane Rl -R' K/ C OOalkyl CH CH2CH2NH2 (III) i CHzCHgCHzNHC 0 CH inaqueous ethanol at room temperature for about two hours in the presenceof a base such as sodium acetate or sodium hydroxide. The thus-obtainedcompound of formula (IX) is extracted with an aromatic hydrocarbonsolvent, preferably benzene, which solvent is then evaporated off invacuo to yield an oily residue of (IX) which is then dissolved inabsolute ethanol and treated with a solution of HCl gas in absoluteethanol, preferably under reflux for about l-5 hours, to yield thedesired indole of formula (V). The foregoing reactions may beillustrated as follows:

(VIII), aq. EtOH NaOc (VII) OH2RI H01 abs. EtOH The following examplesare intended to illustrate, but not to limit, the scope of the presentinvention.

EXAMPLE I Ethyl indoIe-Z-carboxylate (9.84 g., 0.052 mole) is dissolvedin 150 ml. dioxane. Acrylonitrile (3.11 g., 0.0588 mole) andbenzyltrimethylammonium hydroxide (Triton B) (2 ml.) are added and themixture is warmed, with stirring, at 5055 C. for hr. The solution iscooled to room temperature and stirred overnight.

The reaction mixture is added to 500 ml. water containing 3 ml. glacialacetic acid. The mixture is extracted with methylene chloride, theorganic layer washed with 2 X 25 ml. water and dried over magnesiumsulphate. The solvent is removed under reduced pressure. The remainingoil is dissolved in ether and filtered through alumina with ether aseluant. Evaporation of the ether gives a solid. The product obtained isethyl N- (B-cyanoethyl) indole-2-carboxylate; m.p. 8486 C.

EXAMPLE II A 2.42 g. (0.01 mole) quantity of ethyl N-(B- cyanoethyl)indole-2-carboxylate is suspended in acetic anhydride (20 ml. Thesuspended compound is hydrogenated on a Parr shaker in the presence ofRaney nickel. The uptake of hydrogen is complete after 6 1 x-hrs. Theproduct recovered is recrystallized from benzene-hexane. The productobtained is ethyl l-(3- acetamidopropyl) indole-2-carboxylate; m.p.,83.58 45C.

EXAMPLE III Ethyl l-(3-acetarnidopropyl) indole-2-carboxylate (1.44 g.,0.005 mole) is cyclized in the presence of sodium hydride (0.30 g.,0.00625 molar in hydride) in xylene under reflux. A few drops ofabsolute ethanol are added after 1 hr. reflux. Total reflux time is 2hrs. The product recovered is crystallized from benzenehexane. Theproduct obtained is 2,3,4,5-tetrahydrolH-l,4-diazepino [l,2-a]indol-l-one; m.p., l8l-l83 C.

EXAMPLE IV Ethyl N-(B-cyanoethyl) indole-2-carboxylate (29 g., 0.12mole) is dissolved in 200 ml. tetrahydrofuran and treated with ml. (0.09mole) of 1 molar borane solution in tetrahydrofuran. The reactionmixture is stirred for several hours at room temperature and then excessborane is decomposed by careful addition of absolute ethanol.

The reaction mixture is evaporated to dryness in vacuo and the oilyresidue is dissolved in absolute ethanol. The solution is treated withethereal hydrogen chloride and heated under reflux for 1 hr. Thesolution is evaporated to dryness and the residue dissolved in water.The aqueous acid solution is extracted several times with ether and theorganic solutions discarded. The aqueous solution is made alkaline withsodium bicarbonate and extracted with chloroform. The

,chloroform extracts are dried over magnesium sulphate EXAMPLE V Ethyll-(3-aminopropyl) indole-2-carboxylate (25 g.) is dissolved in absoluteethanol and heated under reflux for several hours in the presence of atrace of sodium ethoxide. The solution is evaporated to dryness in vacuoand the residue suspended in water containing enough hydrochloric acidto give an acid reaction to pH paper. The mixture is extracted withchloroform (3 X 50 ml.), the combined extracts are washed once withwater, dried over magnesium sulphate and solvent removed in vacuo. Theresidue is crystallized from chloroform-hexane to give2,3,4,5-tetrahydro-lH-l,4- diazepino 1,2-a] indol-l-one; mp. 18 ll 83 C.

EXAMPLE VI A solution of methyl iodide (3.8 g., 0.040 mole) indimethylformamide (15 ml.) is added to a stirred mixture of2,3,4,5-tetrahydro-lH-l,4-diazepino [l,2-a] indol-l-one (7.2 g., 0.036mole) and potassium t-butoxide (5.3 g.) in dimethylformarnide (45 ml.).The mixture is stirred for an additional 2 hrs. and then diluted withwater (150 ml.). The solid is separated by filtration. Recrystallizationfrom acetone affords 2,3,4,5-tetrahydro-2-methyl-1H-l 4-diazepino 1,2-a]indol-l -one; m.p. 145-l47 C.

EXAMPLE VII Ethyl 5-methoxyindole-2-carboxylate (11 g., 0.05 mole) andacrylonitrile (3.0 g.) are dissolved in ml. dioxane. Triton B (2 ml.) isadded and the mixture is stirred at 55 C. for 3/4 hr., cooled to roomtempera- 108109 C. The product, ethyl -methoxy-N-(,6-

cyanoethyl) indole-2-carboxylate, is towered on alumina andrecrystallized from chloroform-ether; m.p. l121 12.5 C.

I EXAMPLE VIIl v Ethyl 5-methoxy-N-(B-cyanoethyl) indole-2-carboxylate(15.0 g., 0.055rnole) is suspended in acetic anhydride (125 ml.) andhydrogenated on a Parr shaker over Raney nickel. The uptake of hydrogenceases after 5 hrs.; the catalyst is removed by filtration and washedwith absolute ethanol (200 ml). The filtrate is evaporated to dryness invacuo.'The residue is dissolved in chloroform and washed with sodiumhydroxide solution and water. The solution is dried over anhydrousmagnesium sulphate and the solvent is removed in vacuo. The residue iscrystallized from benzene-hexane and affords ethyl 1- (3-acetamidopropyl)-5-methoxyindole-2-carboxylate; m.p. 99.5-101 C.

EXAMPLE IX EXAMPLE X EthylN-(B-cyanoethyl)-5-rnethoxyindole-2-ca.rboxylate (5.44 g., 0.02 mole) isdissolved in 35 ml. tetrahydrofuran. A solution of 16 ml. 1 molar boranein tetrahydrofuran solution is added slowly and the resulting mixture isstirred for several hours at room temperature. Excess borane isdecomposed by careful addition. of absolute ethanol. The solution isevaporated to dryness in vacuo. The oily residue is dissolved inabsolute ethanol. The solution is treated with ethereal hydrogenchloride and heated under reflux for 1 hr. The solution is evaporated todryness. The residue is dissolved in water and the aqueous solution isextracted with ether. The organic extracts are discarded. The aqueoussolution is made alkaline with sodium bicarbonate and extracted withchloroform. The chloroform extracts are dried over magnesium sulphateand solvent is removed in vacuo. The infrared spectrum shows no nitrileabsorption. The product obtained is ethyl 1(3-aminopropyl)-5-methoxy-indole-2-carboxylate. I

EXAMPLE XI Ethyl 1-( 3-aminopropyl)-5-methoxyindole-2- carboxylate, 2.76g. (0.01 mole), is dissolved in 25 ml. ab-

solute ethanol and a solution of sodium ethoxide in ethanol added. Themixture is heated under reflux for 3 hrs., solvent is removed underreduced pressure and the residue is suspended in water containing enoughhydrochloric acid to give an acid solution. The aqueous mixture isextracted with chloroform and the organics are dried over magnesiumsulphate. The solvent is removed. Recrystallization fromchloroform-hexane affords 2,3,4,5-tetrahydro-9-methoxylH-l ,4-diazepino[1,2-a] indol-l-one; m.p. 1'75-'l77 C.

EXAMPLE Xll Ethyl S-chloroindole-2-carboxylate (5 g., 0.0224 mole) andacrylonitrile (1.5 g., 0.028 mole) are mixed with 30 ml. dioxane. TritonB (0.5 ml.) is added and the solution is stirred at 50-55 C. for l hrs.,cooled to room temperature and stirred overnight. The reaction mixtureis poured into water and acidified with glacial acetic acid. The aqueousmixture is extracted with chloroform; the extracts are washed withsodium bicarbonate solution, water, dried over magnesium sulphate andthe solvent is removed in vacuo. The residue is crystallized fromabsolute ethanol to give ethyl 5- chloro-N-(B-cyanoethyl)indole-2-carboxy-late; m.p. 91 .5-93 C.

EXAMPLE XIII A 2.76 g. 0.01 mole) quantity of ethyl 5-chloroindole.N-(B-cyanoethyl)-2-carboxylate is suspended in aceticanhydride (20 ml.). The suspension is hydrogenated on a Parr shaker inthe presence of Raney nickel catalyst. The uptake of hydrogen iscomplete after 2 )6 hrs. The material recovered is crystallized frombenzene-hexane. The product obtained is ethyl 1-( 3-acetamidopropyl)-5-chloroindole- 2-carboxylate; m.p. l30.5l31.5 C.

EXAMPLE XIV Ethyl 1-( S-acetamidopropyl )-5 -chloroindole-2-carboxylate(1.63 g., 0.005 mole) is cyclized in the presence of sodium hydride(0.30 g., 0.00625 molar in hydride) in xylene under reflux. A few dropsof ethanol are added after 1 hr. reflux. The total reflux time is 2 hrs.The material recovered is crystallized from chloroform-hexane. Theproduct obtained is 9-chloro- 2,3,4,5-tetrahydro l H-l, 4-diazepino-[1,2-a]-indol-1- one; m.p. 222-223 C.

EXAMPLE xv Ethyl N-(B-cyanoethyl)-5-chloroindole-Z-carboxylate (2.76 g.,0.01 mole) is dissolved in 20 ml. tetrahydrofuran and treated with 10ml. 1 molar borane in tetrahydrofuran solution. The mixture is stirredfor a further 2 hrs. and excess borane decomposed with absolute ethanol.The solution is evaporated to dryness in vacuo, dissolved in water andextracted with ether. The organic extracts are discarded. The aqueoussolution is made alkaline with sodium bicarbonate and extracted withchloroform. The chloroform extracts are dried over magnesium sulphateand solvent is removed in vacuo. The infrared spectrum shows no nitrileabsorption. The product obtained is ethyl 1-( 3-aminopropyl)-5-chloroindole-2-carboxylate.

EXAMPLE XVI Ethyl l-( 3-aminopropyl )-5-chlorindole2-carboxylate EXAMPLEXVII Methyl iodide (3 ml., 4.5 g.) in 20 ml. dimethylformamide is addedto a stirred suspension of 9-chloro-2,3,4,5-tetrahydro-lI-I-1,4-diazepino [1,2-a] indol-lone (4.69 g., 0.02mole) and potassium t-butoxide (3.0 g., 0.0267 mole) in 50 ml.dimethylformamide. It is necessary to keep the temperature of thereaction mixture below 35 C. by cooling in a water bath. The mixture isstirred at room temperature for 2 hrs. and then poured onto 250 ml.water. The solid which separates is removed by filtration.Recrystallization from acetone affords 9-chloro-2,3 ,4,5-tetrahydro2-methyl- 1 I-I-l ,4 diazepino [1,2-a] indol-1one;m.p.188-189.5 C.

EXAMPLE XVIII 9-Chloro-2,3,4,5-tetrahydro- 1 H-l ,4-diazepino-[ 1 ,2-

a] indol-lone (2.82 g., 0.012 mole) is dissolved in drydimethylformamide (30 ml.) and treated with potassium t-butoxide (1.8g.). A solution of ethyl iodide (2.6 g., 0.0167 mole) indimethylformamide ml.) is added at such a rate as to keep thetemperature below 35 C. The mixture is stirred for a further hour afterad dition is complete. The reaction mixture is poured onto 100 ml. waterand the solid which separates is removed by filtration and isrecrystallized from acetone. 9- Chloro-2-ethyl-2,3 ,4,5-tetrahydro-1H-l4-diazepino [1,2-a] indol- 1 -one is obtained; m.p. 183-185 C.

EXAMPLE XIX 9-Chloro-2,3,4,5tetrahydro- 1 H- 1 4-diazepino 1 ,2- a]indol-l-one (2.35 g., 0.01 mole) is dissolved in 25 ml. drydimethylformamide and treated with potassium t-butoxide (1.5 g.). a-Bromo-p-xylene (2.5 g., 0.0135 mole) in 20 ml. dimethylformamide isadded slowly with stirring at a temperature below 35 C. When addition iscomplete, the mixture is stirred for 3 hrs. at room temperature, pouredonto water and filtered. The resulting solid is dissolved in chloroform;the solution is dried over magnesium sulphate and solvent is removed.The residue is recrystallized from acetone to give 9-chloro-2,3,4,5-tetrahydro-2-(p-tolyl) methyl- 1 I-I-l 4- diazepino1,2-a] indol- 1 -one; m.p. 147149 C.

EXAMPLE XX 2,3 ,4,5-Tetrahydro-9-methoxy- 1 H-l 4-diazepino [1,2-a]indol-l-one (9.4 g., 0.04 mole) is added to a slurry of 2.4 g. of 50percent sodium hydride (approximately 0.05 molar in sodium hydride) in200 ml. toluene. The mixture is stirred under reflux for 2 hrs, and asolution of freshly distilled dimethylaminopropylchloride (7.29 g., 0.06mole) in 50 ml. toluene is added. Heating is continued for 3 hrs. andthe mixture is cooled to room temperature and stirred overnight. Theprecipitate is separated by filtration and the filtrate is evaporated todryness. The oil formed is converted to the hexamate. This compound isrecrystallized from absolute ethanol-ether. The product is2-(dimethylaminopropyl)-2,3,4,5- tetrahydro-9-methoxy-1H-l 4-diazepino1.2-a] indoll-one hexamate; m.p. l32-l34 C.

EXAMPLE XXI A mixture of 9-chloro-2,3,4,5-tetrahydro-lH-l, 4- diazepino[1,2-a] -indol-l-one (5.3 g., 0.023 mole), potassium t-butoxide (3.4 g.,0.03 mole) and 30 ml. of dimethylformamide is stirred at roomtemperature. To the stirring solution, N, N-dimethyl chloroacetamide(3.6 g., 0.03 mole) in 25 ml. of dimethylformamide is added dropwise.The mixture is stirred an additional 1 5% hrs. and then is treated withwater. The solid is filtered and recrystallized from chloroform-hexane.The product obtained is 9-chloro-2,3,4,5-tetrahydro-N, N-dimethyl-l-oxo-lI-I-l, 4-diazepino [1,2-a] indole-2- acetamide; rn.p.183l85C.

EXAMPLE XXII A suspension of 9-chloro-2,3,4,5 tetrahydro-lH-l, 4-diazepino [1,2-a] indol-l-one (4.69 g., 0.02 mole) and 1.2 g. 50 percentsodium hydride in toluene ml.)

.is stirred under reflux for 2 hrs. Freshly distilleddimethylaminoethylchloride (3.22 g., 0.03 mole) in 10 ml. toluene isadded. The mixture is heated under reflux for an additional 3 hrs. Themixture is cooled to room temperature, filtered, and the solvent isremoved in vacuo. Ethereal hydrogen chloride is added to an ethanolsolution of this solid. Several recrystallizations from ethereal ethanolare undertaken. The product obtained is9-chloro-2-dimethylaminoethyl-2,3,4,5- tetrahydro-lH-l, 4-diazepino[1,2-a] indol-l-one hydrochloride; m.p. 236237 C.

EXAMPLE XXIII By substituting an equivalent amount of thel-oxodiazepinoindole product obtained from Example V and Example XI forthe 9-chloro-l-oxo-diazepinoindole used in Examples XXI and XXII, andrepeating the procedures of the latter two examples, there are obtainedas respective products:

2,3 ,4,5-tetrahydro-N,N-dimethyl- 1 -oxol H-1 ,4-

diazepino[ 1.2a] indole-2-acetamide; 9-methoxy-2,3,4,5-tetrahydro-N,N-dimethyll -oxolI-I-l ,4-diazepino[ 1,2a]indole-2-acetamide; 2-dimethylaminoethyl-2,3,4,5-tetrahydro- 1 11-1,4-

diazepino[ l,2a]indol- 1 -one hydrochloride; and9-methoxy-2-dimethylaminoethyl-2,3,4,5-

tetrahydro- 1 -H- l ,4-diazepino 1 ,2a]indol-1-one hydrochloride.

EXAMPLE XXIV The procedure of Example XIX is repeated except that anequivalent amount of benzyl bromide is used as the alkylating agentinstead of a-bromo-p-xylene, and an equivalent amount of an appropriatediazepinoindole is used as the material to be alkylated, to yield thefollowing products:

0104) Inn:

EXAMPLE XXV A. Aniline (27.9 g., 0.3 moles) is dissolved in 300 ml.percent hydrochloric acid and 300 g. ice and diazotized with a solutionof sodium nitrite (22.5 g.) in 60 ml. ice water. The diazonium saltsolution is added rapidly to a stirred mixture of ethyla-ethylacetoacetate (50.6 g., 0.32 mole), 300 g. ice, 300 ml. absoluteethanol and 246 g. sodium acetate. The mixture is stirred for 2 hrs. andextracted with benzene. The benzene extract is washed with water, dried.over magnesium sulphate and the solvent removed in vacuo. The residualoil is dissolved in 60 ml. absolute ethanol and treated with 150 ml.ethanolic hydrogen chloride. When the exothermic reaction has subsided,the mixture is heated under reflux for 2 hrs. and then cooled to roomtemperature. The mixture is diluted with water and the solid separatedby filtration and triturated with chloroform. The chloroform mixture isdried and evaporated to give ethyl 3-methylindole-2-carboxylate as anoff-white solid, m.p. 134.5l36 C.

B. The procedure of Example XXV-A is repeated except that an equivalentquantity of ethyl abenzylacetoacetate and ethyl a-propylacetoacetate issubstituted for the ethyl a-ethylacetoacetate used therein to yield, asrespective products, ethyl 3-phenylindole-2-carboxylate and ethyl3-ethylindole-2-carboxylate.

EXAMPLE XXVI A. Ethyl 3-methylindole-Z-carboxylate (39.1 g., 0.192 mole)is dissolved in dioxane (250 ml.) followed by the addition ofacrylonitrile (12 g., 0.22 mole) and Triton B (5 ml.). The mixture isstirred at 5060 C for 7 hrs. and then at room temperature overnight. Thereaction mixture is poured into water made acidic with acetic acid. Thismixture is extracted with chloroform and the chloroform extracts arewashed with sodium bicarbonate and water, dried over sodium sulfate andevaporated in vacuo. The resulting oil is crystallized andrecrystallized from aqueous ethanol to afford ethylN-(B-cyanoethyl)-3-methylindole-2-carboxylate as a pale yellow solid(mp. 56.558 C).

B. By substituting an equivalent quantity of each of the esters obtainedfrom Example XXV-B in the cyanoethylation procedure described in ExampleXXVI-A, there are obtained, as respective products, the 3-phenyl and3-ethyl derivatives of ethyl N-(ficyanoethyl)-indole-2-carboxylate.

EXAMPLE XXVII A. Ethyl 3-methyl-N-(B-cyanoethyl)indole-2-carboxylate(58.0 g., 0.22 mole) is suspended in acetic anhydride (400 ml.) andhydrogenated on a Parr shaker over Raney nickel. After the uptake ofhydrogen ceases, the catalyst is separated by filtration and washed withabsolute ethanol. The combined filtrates are evaporated to dryness invacuo. The residue is dissolved in chloroform and washed with sodiumhydroxideto remove any residual acetic anhydride and then washed withwater. The chloroform layer is dried over magnesium sulfate and thesolvent removed in vacuo. The residual material is dissolved in benzene(50 ml.) and chromatographed on Woelm neutral alumina. Elution withbenzene-chloroform (lzl) afiords ethyl l-(3-acetamidopropyl)-3-methyl-2-carboxylate as a white solid, mp. l l0-l13C.

B. The reductive amidation procedure of Example XXVII-A is repeatedusing an equivalent quantity of each of the products obtained fromExample XXVI-B to yield, as respective products, the 3-phenyl and 3-ethyl derivatives of ethyl l-(3-acetamidopropyl)-indole-2-carboxylate.

EXAMPLE XXVIII A. Ethyl 1 (3-acetylaminopropyl)-3-methylindole-2-carboxylate (20 g., 0.066 mole) is added to a suspension of sodiumhydride (3.9 g., 0.16 mole) in dry xylene (280 ml.) and the mixtureheated under reflux for 5 hrs. The reaction mixture is poured onto waterand the resulting yellow precipitate is separated and dissolved inchloroform. The chloroform solution is washed with water, dried overmagnesium sulfate and evaporated in vacuo. The resulting solid isrecrystallized from chloroform-hexane to give 2,3,4,5-tetrahydro-llmethyl-lH-l ,4-diazepino [l,2-a]indol-l-one as a white solid, mp. 22 l-222 C.

B. In accordance with the cyclization procedure outlined in ExampleXXVII-A, except that an equivalent quantity of each of the estersobtained from Example XXVII-B is substituted for the ethyl l-(3-acetylaminopropyl)-3-methylindole-2-carboxylate used therein, thefollowing respective products are obtained: 2,3,4,5-tetrahydro-ll-phenyl-lH-1,4-diazepino[ l ,2-

a] indol- 1 -one; and 2,3,4,5-tetrahydro-l l-ethyll H-l,4-diazepino[1,2- a]indol-1-one.

EXAMPLE XXIX By repeating the procedure of Example XXV-A, except that anequivalent quantity of p-chloroaniline is substituted for the anilineused therein, ethyl 5-chloro- 3-methylind0le-2-carboxylate is obtainedas the product, m.p. 163.5165 C.

EXAMPLE XXX Ethyl 5-chloro-3-methylindole-2-carboxylate (38 g., 0.16mole) is dissolved in dioxane (300 ml.), followed by the addition ofacrylonitrile 10.8 g., 0.19 mole) and Triton B (5 ml.). The mixture isstirred at 50-60 C for 4-% hrs., then at room temperature overnight. Thereaction mixture is poured into water made acidic with acetic acid. Theresulting solid is filtered off and dissolved in chloroform and thechloroform solution is washed with sodium bicarbonate and water, driedover sodium sulfate, and evaporated in vacuo. The resulting oily residueis crystallized and recrystallized from ethanol to yield ethyl5-chloro-N-(B-cyanoethyl)-3- methyl-indole-2-carboxylate as an off-whitesolid, m.p. l03-l 05 C.

EXAMPLE XXXI The method of Example XXVII-A is repeated except that ethyl-chloro-N-(B-cyanoethyl)-3-methylindole- Z-carboxylate (24 g., 0.083mole) is suspended in acetic anhydride (250 ml.). The uptake of hydrogenis complete after 5-% hrs. Work-up of thereaction mixture gives an oilthat is crystallized from aqueous ethanol to yield ethyll-(acetamidopropyl)-5-chloro-3- methylindole-2-carboxylate as a whitesolid in about 80 percent yield, m.p. l 12l 14 C.

EXAMPLE XXXII Ethyl 1 acetamidopropyl)-5-chloro-3-methylindole-2-carboxylate (13.7 g., 0.041 mole) is addedto a suspension of sodium hydride (2.1 g., 0.045 mole) in dry xylene(150 ml.) and the mixture is heated under reflux for 6 hrs. The reactionmixture is filtered and the filtrate evaporated. The residue obtained isstirred with water and extracted with chloroform. The chloroformextracts are washed with 2N hydrochloric acid, then water, dried overmagnesium sulfate and evaporated in vacuo. The resulting yellow solid isrecrystallized from aqueous ethanol to yield9-chloro-2,3,4,5-tetrahydro- 1 l-methyl-lH-l ,4-diazepino[ l,2-a]indol-1-one, m.p. l54-155.5 C.

EXAMPLE XXXIII The indole synthesis procedure described in Example XXV-Amay be used to prepare the compounds of formula (V). Accordingly, byusing equivalent quantities of an appropriately substituted aniline andan appropriately substituted acetoacetate, the following indoles areobtained: methyl 5-fluoroindole-2-carboxylate; ethyl5-fluoro-3-methylindole-2-carboxylate; ethyl5-chloro-3-phenylindole-2-carboxylate; methyl5-ethoxy-3-ethylindole-2-carboxylate; ethyl5-methoxy-3-phenylindole-2-carboxylate; and methyl5-fluoro-3-ethylindole-2-carboxylate.

EXAMPLE XXXIV By using an equivalent quantity of each of the indolesprepared in Example XXXII! in the cyanoethylation procedure described inExample XXVI-A, the following respective products are obtained: methylN-(B-cyanoethyl)-5-fluroindole-2-carboxylate; ethylN-(B-cyanoethyD-S-fluoro-3-methylindole-2-carboxylate; ethylN-(B-cyanoethyl )-5 -chloro-3-phenylindole-2-carboxylate; methylN-(B-cyanoethyl)-5-ethoxy-3-ethylindole-carboxylate; ethylN-(B-cyanoethyl)-5-methoxy-3-phenylindole-2- carboxylate; and methylN-(B-cyanoethyl)-5-fluoro-3-ethylindole-2-carboxylate.

EXAMPLE XXXV The reductive amidation procedure of Example XXVlI-A may befollowed to prepare the acetamidopropyl indoles of formula (ll). Forexample, by starting with an equivalent quantity of each of the indoleesters obtained from Example XXXIV, the following respective productsare obtained: methyl 1( 3-acetamidopropyl)-5-fluoroindole-2-carboxylate; ethyl l-( 3-acetamidopropyl)-5-fluoro-3-methylindole- 2-carboxylate;

14 ethyl l-(3-acetamidopropyl)-5-chloro-3-phenylindole- 2-carboxylate;methyl l-( 3-acetamidopropyl )-5-eth0xy-3-ethylindolecarboxylate; ethyll 3-acetamidopropyl )-5 -methoxy-3-phenylindole-2-carboxylate; and Imethyl l-( 3-acetamidopropyl )-5 -fluoro-3-ethylindole- 2-carboxylate.

EXAMPLE xxxvl The cyclization procedure of Example XXVlll-A is repeatedwith an equivalent quantity of each of the indole esters obtained fromExample XXXV to yield as respective products:

1,2a]indol- 1 -one;

2,3 ,4,5-tetrahydro-9-fluoro-l l-methyll H-1 ,4-

diazepino[ 1 ,2a]indol- 1 -one;

2,3 ,4,5-tetrahydro-9-chloro-1 l-phenyll H-1 ,4-

diazepino[1,2a]indol-l-one;

2,3,4,5-tetrahydro-9-ethoxy-l l-ethyll H-1 ,4-

diazepino[ l ,2a]indol-l-one;

2,3 ,4,5-tetrahydro-9-methoxy-1 l-phenyl-l H- l ,4-

diazepino[ l,2a]indol- 1 -one; and

2,3 ,4,5-tetrahydro-9-fluoro-l l-ethyl- 1 H- l ,4-

diazepino[ l ,2a]indol- 1 -one.

EXAMPLE XXXVII The alkylation procedures described in Examples XVIIthrough XXII may be followed to prepare the N- alkylated derivatives offormula (I-a). Accordingly, by using equivalent quantities of anappropriate alkylating agent and an appropriate l-oxo-2-unsubstituteddiazepinoindole as the material to be alkylated, the followingderivatives of 2,3,4,5-tetrahydro-lH-l ,4- diazepino[ l ,2aindol- 1 -oneare prepared:

2,3 ,4,5 -tetrahydro-l l-methyll H-l ,4-diazepino[ l ,2- a]-indol-l-one(7.7 g., 0.036 mole) is added to a suspension of lithium aluminumhydride (1.6 g.) in dry monoglyme (250 ml.) and heated under reflux for23 hrs. Ice is added to decompose any remaining lithium aluminumhydride. The precipitate is separated by filhydrobromide salt, upon.recrystallization from methanol-ether, has a m. p. of 25825 9 C.

EXAMPLE XXXIX 2,3 ,4,5-tetrahydrol H- l ,4-diazepino[ l ,2-a]indoll one(6.0 g., 0.03 mole) in 200 ml. of monoglyme is adapted dropwise to astirred suspension of lithium aluminum' hydride (2.8 g., 0.08 mole) in220 ml. of monoglyme, and the'mixture heated under reflux overnight.Water is added to the cooled mixture, and the mixture filtered. Thefiltrate is dried with anhydrous magnesium sulfate and concentrated invacuo, giving an oil which solidifies on standing to give about 85percent theoretical yield of the free amine, 2,3,4,5-tetrahydro-1H-1,4-diazepino[ l ,2a]indole, m.p. 75-77 L C. The hexamate,recrystallized from methanol-ether is an off-white solid, m.p. l70172 C.

EXAMPLE XL By repeating the reduction procedure of Example XXXIX, exceptthat an equivalent quantity each of the 2-methyl, the 9-chloro, the9-methoxy and the 9- chloro-1l-methyl derivative of2,3,4,5-tetrahydro-1H- 1,4-diazepino[l,2a]indol-1-one is employed as thematerial to be reduced, the following respective products are obtained:

2,3 ,4,5-tetrahydro-2-methyl- 1 H- 1 ,4-diazepin[ 1,2a]indole (m.p.98100 C.);

9-chloro-2,3 ,4,5-tetrahydrol H-l ,4-diazepino[ 1,2a]indole (m.p. 88-90C.) and its corresponding hexamate salt (m.p. 170-l72 C., uponrecrystallization from ethanol);

9-methoxy-2,3 ,4,5 -tetrahydro-1H- l ,4-diazepino[ 1,2a]indole (m.p.1l01 12 C.) and its corresponding hexamate salt (m.p. l63165 0, uponrecrystallization from ethanol); and

9-chloro-2,3 ,4,5-tetrahydro-1 l -methyl-1 H- 1 ,4-

diazepino[1,2a]-indole (m.p. of HCl salt: 269-2 71C.).

EXAMPLE XLI over magnesium sulphate and solvent removed in 60 vacuo togive an amber oily residue of the reduced product,2-[3-(dimethylamino)propyl]-2,3,4,5- tetrahydro-Q-methoxy- 1 H4,4-diazepino[ l ,2-a] indole. Conversion to the hexamate salt andrecrystallization twice from acetone yields off-white crystals of 2-[3-65 (dimethylamino)propyl]2,3,4,5-tetrahydro-9-methoxy- 1 H-l,4-diazepino[ 1 ,2-a]indole dihexarnate hydrate, m.p. l32-134 C.

16 EXAMPLE XLI] A. The foregoing procedures of Examples XXXVlll throughXLI demonstrate the reduction of formula (l-a) compounds to thecorresponding formula (l-b) compounds. Accordingly, by following suchprocedures, except that an equivalent quantity of an appropriate l-oxodiazepinoindole is employed as the material to be reduced, the followingrespective derivatives of 2,3,4,5-tetrahydro-l H- l ,4-diazcpinol 1,211]indole are obtained:

B. By following the reduction procedures of Examples XXXVIII throughXLI, except that an equivalent quantity of each of the l-oxo-2-R-9-R-1l-R' diazepinoindoles prepared in Example XXXVII (excluding thosewherein R is a di-(lower alkyl)- amidomethyl substituent) is used as thestarting material to be reduced, there are obtained, as respectiveproducts, the corresponding 2-R"-9-R-l1-R derivatives of 2,3,4,5-tetrahydro-1H-1 ,4-diazepino[ l ,2a]indole (I-b).

EXAMPLE XLIII 2,3 ,4,5-tetrahydro-1 1 -methyl-1H-l ,4-diazepino[ l ,2-a]-indole (3 g., 0.015 mole) is dissolved in acetic anhydride (10 ml.)and heated on a steam bath for 1 hr. The reaction mixture is then pouredinto dilute sodium hydroxide and stirred, the resulting solid wasfiltered and taken up in chloroform. The chloroform solution is driedover magnesium sulfate and evaporated in vacuo. Recrystallization of theresidue from benzene-hexane yields 2-acetyl-2,3,4,5-tetrahydro-11-methyllH-l,4- diazepino[ l ,2-alindole, m.p. l -162 C.

EXAMPLE XLIV 9-chloro-2,3,4,5-tetrahydro-1H-1 ,4-diazepino[ l ,2-a]-indole (6.6 g., 0.03 mole) is heated on a steam-bath for 3 hrs. with50 ml. acetic anhydride. The reaction mixture is concentrated underreduced pressure, dissolved in chloroform and shed with sodium hydroxidesolution. The organic layer is washed with water and dried overanhydrous magnesium sulphate. Removal of the solvent in vacuo andcrystallization of the resulting oil from aqueous ethanol affords2-acetyl-9-chloromime 030R EXAMPLE XLV 9-chloro-2,3,4,5-tetrahydrol H-l,4-diazepino[ l ,2- a]-indole (4.0 g., 0.0181 mole) is dissolved in 200ml. acetone containing 20 g. anhydrous potassium carbonate. Butyrylchloride (2.0 g., 0.0192 mole) is added and the mixture is stirredovernight at room temperature. The precipitateis removed by filtrationand washed with chloroform. The washings and the acetone filtrate arecombined and evaporated in vacuo. The residue is dissolved in chloroformand the solution washed successively with dilute hydrochloric acid,water, dilute sodium hydroxide and water and then dried over magnesiumsulphate. Removal of the solvent affords an amber oil that is purifiedby filtration through alumina (chloroform-ether, 1:1, as eluant) andcrystallized from benzene-hexane as a pale yellow solid,2-butyryl-9-chloro-2,3 ,4,5-tetrahydro- 1 PM ,4- diazepino[ l,2-a]indole, mp. l l4-1 15 C.

EXAMPLE XLVI 9-chloro-2,3,4,5-tetrahydro-l l-methyl-l H-1 ,4-diazepino[l,2-a]indole (4 g., 0.017 mole) is dissolved in aceticanhydride (20 ml.) and heated on a steam bath for 1 hr. The reactionmixture is poured onto dil. sodium hydroxide and stirred. This mixtureis extracted with chloroform and the chloroform extract is dried overmagnesium sulfate and evaporated in vacuo to give a dark oil. The oil isdissolved in 5 ml. benzene and chromatographed on 50 g. Woelm neutralalumina (activity grade l) the elution being carried out with benzene.The solid obtained is recrystallized from aqueous ethanol to yield2-acetyl-9-chloro-2,3,4,5- tetrahydro-l l-methyll H- 1 ,4-diazepino[ l,2-a]indole as a white powder, m.p. l20-l 22 C.

EXAMPLE XLVII The procedures of Examples XLIII through XLVI demonstratethe general method of acylating the 9-R- ll-R-2-unsubstituted compoundsof formula (I-b) to yield the corresponding 2-lower alkanoylderivatives. Accordingly, by following such procedures, except thatequivalent quantities are used of an appropriate acylating agent and anappropriate 2-unsubstituted formula (I-b) compound to be acylated, thefollowing respec-- tive products are obtained:

N (lwer alkanoyl) Compound No. R R Alkanoyl XLVII-a H H acetyl b H Hisopropionyl c MeO H acetyl d MeO H n-but'yryl e H Me n-butyryl f Cl Meisopropionyl g F H acetyl h F Me acetyl i Cl Ph n-propionyl j EtO Etacetyl k MeO Ph acetyl I F Et n-butyryl We claim: I

l. A lower alkyl l-('3-acetamidopropyl)-3-R-5 R-indole-2-carboxylatehaving the formula:

\ HCOO-(lower alkyl) CHzCI-IzCHzNHC OCH;

wherein R is a member selected from the group consisting of hydrogen,lower alkoxy, chloro and fluoro.

4. The carboxylates of claim 3 wherein lower alkyl is ethyl.

5. A lower alkyl l-cyanoethyl-3-phenyl-5-R-indole- 2-carboxylate havingthe formula:

R phenyl N [0 O O-(lower alkyl) wherein R is a member selected from thegroup consisting of hydrogen, lower alkoxy, chloro and fluoro.

6. The carboxylates of claim 5 wherein lower alkyl is ethyl.

2. The carboxylates of claim 1 wherein lower alkyl is ethyl.
 3. A loweralkyl 1-(3-aminopropyl)-3-phenyl-5-R-indole-2-carboxylate having theformula: wherein R is a member selected from the group consisting ofhydrogen, lower alkoxy, chloro and fluoro.
 4. The carboxylates of claim3 wherein lower alkyl is ethyl.
 5. A lower alkyl1-cyanoethyl-3-phenyl-5-R-indole-2-carboxylate having the formula:wherein R is a member selected from the group consisting of hydrogen,lower alkoxy, chloro and fluoro.
 6. The carboxylates of claim 5 whereinlower alkyl is ethyl.